Thienodiazepine compounds and their pharmaceutical use

ABSTRACT

Thienodiazepine compounds of the general formula ##STR1## wherein R 1  and R 2  are the same or different and respectively stand for a hydrogen atom, a halogen, an alkyl or an aralkyl, or mean a group wherein R 1  and R 2  combinedly together form a ring; R 3  stands for an oxygen atom, R 4  stands for a hydrogen atom, an alkyl, an alkenyl or a group of the formula --(CH 2 ) m  COOR 6  (wherein R 6  l stands for a hydrogen atom, an alkyl, an alkenyl or an aralkyl and m stands for an integer of 1-6), or R 3  and R 4  stand for a group wherein R 3  and R 4  combinedly together form a group of the formula ═N--N═C(R 5 )-- [wherein R 5  stands for a hydrogen atom, an alkyl, an alkenyl, an aralkyl or a group of the formula --(CH 2 ) n  COOR 7  (wherein R 7  stands for a hydrogen atom, an alkyl, an alkenyl or an aralkyl and n stands for an integer of 1-6)]; Ar and X are the same or different and respectively stand for an aryl or a heteroaryl; and p stands for an integer of 1-6, and their salts and their pharmaceutical use. 
     These compounds possess an antagonistic action to cholecystokinin and gastrin and exhibit a durable pancreatic enzymes- and gastric acid-secretion-suppressive action, and therefore are useful as the medicaments acting on the central nervous system and peripheral nervous system and as the prophylactic or therapeutic medicines for pancreatic disorders and gastrointestinal ulcers.

TECHNICAL FIELD

This invention relates to thienodiazepine compounds and their saltswhich are novel and useful as medicaments, and to their pharmaceuticaluse.

BACKGROUND OF THE ART

In the specification of U.S. Pat. No. 3,849,405, it is disclosed thatsome kinds of thieno[2,3-e]-1,4-diazepine compounds possess centralnervous actions such as an antidepressive action and an anticonvulsiveaction. In the specification of U.S. Pat. No. 3,904,641, it is disclosedthat a certain kind of s-triazolo[3,4-c]thieno[2,3-e][1,4]diazepinecompound has a useful pharmacological activity on the central nervoussystem such as an antidepressive activity and an anticonvulsiveactivity.

Meanwhile, as the substances which exist in the gastro-intestinaltissues and central nervous system and which are concerned with thecontrol of the secretion of pancreatic enzymes and gastric acid, knownare cholecystokinin (referred to also as CCK) which is a neuropeptideconsisting of 33 amino acids and gastrin consisting of 34 amino acids.In connection with CCK, CCK-8 which consists of the 8 amino acids at theC terminus of CCK also possesses the same actions. Also, pentagastrinwhich consists of the 5 amino acids at the C terminus of gastrinpossesses the same actions. The amino acid sequence of pentagastrin isidentical with that at the C terminus of CCK.

Since the substances which exhibit an antagonistic action to these CCKand gastrin are effective in the prophylaxis and therapy of suchdiseases as pancreatic disorders and gastrointestinal ulcers, a numberof such antagonistic substances have been studied so far. As anantagonistic substance to CCK, benzotripto is known [Proc. Natl. Acad.Sci. U.S.A., vol. 78, p. 6304 (1981)], and progulmide is known as anantagonistic substance to gastrin, [J. Med. Chem., vol. 27, p. 1597(1984)]. Their actions are, however, relatively weak, and therefore,compounds having higher activities have been desired.

Besides, peptide antagonistic substances are not altogether satisfactoryin that the durability of their actions is short and in that they areunstable and are not absorbed fully.

DISCLOSURE OF THE INVENTION

After the present inventors had conducted intensive studies for thepurpose of creating substances which displayed effective antagonisticactions to CCK and gastrin and were useful as medicaments, they found acertain kind of thienodiazepine compound attained the purpose, whichculminated in the completion of the present invention.

That is, this invention is to provide thienodiazepine compounds of thegeneral formula ##STR2## wherein R¹ and R² are the same or different andrespectively stand for a hydrogen atom, a halogen, an alkyl or anaralkyl, or mean a group wherein R¹ and R² combinedly together form aring; R³ stands for an oxygen atom, R⁴ stands for a hydrogen atom, analkyl, an alkenyl or a group of the formula --(CH₂)_(m) COOR⁶ (whereinR⁶ stands for a hydrogen atom, an alkyl, an alkenyl or an aralkyl and mstands for an integer of 1-6), or R³ and R⁴ stand for a group wherein R³and R⁴ combinedly together form a group of the formula ═N--N═C(R⁵)--[wherein R⁵ stands for a hydrogen atom, an alkyl, an alkenyl, an aralkylor a group of the formula --(CH₂)_(n) COOR⁷ (wherein R⁷ stands for ahydrogen atom, an alkyl, an alkenyl or an aralkyl and n stands for aninteger of 1-6)]; Ar and X are the same or different and respectivelystand for an aryl or a heteroaryl; and p stands for an integer of 1-6,or their salts.

Also, the present invention is to provide pharmaceutical compositionscontaining a thienodiazepine compound of the above-mentioned generalformula (I) or a salt thereof.

In the foregoing definition and the present specification, the halogenmeans chlorine, bromine, fluorine or iodine; the alkyl means an alkylhaving 1-20 carbon atoms such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tertbutyl, pentyl, isopentyl, tert-pentyl, hexyl,octyl, 2-ethylhexyl, 1,1,3,3-tetramethylbutyl, nonyl, decyl, dodecyl,tetradecyl, octadecyl or eicosyl; the alkenyl means an alkenyl having 2to 8 carbon atoms such as vinyl, 1-propenyl, allyl, isopropenyl,2-butenyl, 2-pentenyl, 3-hexenyl or 6-octenyl; the alkoxy means analkoxy having 1-20 carbon atoms such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy,octyloxy, decyloxy, dodecyloxy, octadecyloxy or eicosyloxy; the aralkylmeans a benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl,4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl or the like which mayhave, on the aromatic ring, one to three substituent(s) selected fromamong halogens, alkyls, alkoxys, trifluoromethyl, nitro, amino, cyanoand hydroxy group; the aryl means a phenyl, a 1-naphthyl, a 2-naphthylor the like which may have, on the aromatic ring, 1-3 substituent(s)selected from among halogens, alkyls, alkoxys, trifluoromethyl, nitro,amino, cyano and hydroxy group; the heteroaryl means a pyridyl(2-pyridyl, 3-pyridyl, 4-pyridyl), a quinolyl (e.g. 2-quinolyl,3-quinolyl), an indolyl (e.g. 2-indolyl, 3-indolyl), a thienyl(2-thienyl, 3-thienyl), a furyl (2-furyl, 3-furyl), a benzofuranyl (e.g.2-benzofuranyl, 3-benzofuranyl), a 1H-benzimidazol-2-yl, a2-benzothiazolyl or the like which may have, on the ring, one to threesubstituent(s) selected from among halogens, alkyls, alkoxys,trifluoromethyl, nitro, amino, cyano and hydroxy group; the ring formedcombinedly together by R¹ and R² means a cyclopentene ring, acyclopentadiene ring, a cyclohexene ring, a cyclohexadiene ring, abenzene ring, a cycloheptene ring, a cycloheptadiene ring, acycloheptatriene or the like.

As the salts of the compounds of the general formula (I), mention can bemade of acid addition salts with inorganic acids or organic acids andsalts with inorganic bases, organic bases or amino acids. From thepurposes of the present invention, nontoxic salts are preferable.

Since the compounds of the general formula (I) have at least one chiralcarbon atom, they can exist as a racemic body, an optically activeisomer or a diastereomer, all of which are encompassed in the presentinvention.

The compounds of the general formula (I) of the present invention can beproduced by reacting a compound of the general formula ##STR3## whereineach of the symbols is as defined above with a compound of the generalformula

    X--CO--Z                                                   (III)

wherein X is as defined above and Z stands for a leaving group [hydroxygroup, a halogen, an ester residue (e.g. pentachlorophenoxy,p-nitrophenoxy), a thioester residue (e.g. phenylthio,2,6-dimethylpyridine-4-thio), etc.].

The reaction usually proceeds in a solvent inert to the reaction (water,methanol, ethanol, tetrahydrofuran, diethyl ether, dioxane,dichloromethane, chloroform, ethyl acetate, benzene, toluene,dimethylformamide, dimethylacetamide, acetic acid, etc. or a mixedsolvent thereof) at a temperature ranging from about -20° C. to theboiling point of the solvent used, in the presence of a base or adehydrating-condensing agent if necessary, for about 30 minutes to 24hours.

As the base to be used as necessary, mention is made of alkali metalhydroxides (sodium hydroxide, potassium hydroxide, etc.), alkali metalcarbonates (sodium carbonate, potassium carbonate, etc.), alkali metalhydrogencarbonate (sodium hydrogencarbonate, potassiumhydrogencarbonate, etc.), alkali metal hydrides (sodium hydride, etc.),and organic bases (triethylamine, pyridine, picoline,N-methylmorpholine, etc.). The reaction can be conducted by using aphase transfer catalyst such as tetrabutylammonium bromide orbenzyltriethylammonium iodide and an alkali metal hydroxide in atwo-phase solvent consisting of an organic solvent mentioned above andwater. As the dehydrating-condensing agent, preferred aredehydrating-condensing agents usable for amide synthesis, which areexemplified by dicyclohexylcarbodiimide, N-methyl-2-chloropyridiniumiodide, molecular sieve and the like.

The compounds of the formula (I) wherein R³ and R⁴ combinedly form agroup of the formula forming ═N--N═C(R⁵)-- can be produced by reacting acompound (I) wherein R³ is an oxygen and R⁴ is a hydrogen atomrepresentable by the formula ##STR4## wherein each of the symbols is asdefined above with a thionation reagent to obtain a compound of thegeneral formula ##STR5## wherein each of the symbols is as definedabove, followed by the reaction of this compound of the general formula(V) with a compound of the general formula

    R.sup.5 CONHNH.sub.2                                       (VI)

or alternatively by the reaction of the compound of the general formula(V) with hydrazine hydrate to obtain a compound of the general formula##STR6## wherein each of the symbols is as defined above, followed bythe reaction of the compound (VII) with a compound of the generalformula

    R.sup.5 COOH                                               (VIII)

wherein R⁵ is as defined above or its reactive derivative or with acompound of the general formula

    R.sup.5 C(OR.sup.8).sub.3                                  (IX)

wherein R⁸ stands for an alkyl such as methyl or ethyl and R⁵ is asdefined above.

As the thionation reagent to be used for the above-mentioned method,mention is made of phosphorus pentasulfide, Lowesson reagent[2,4-bis(4-methoxyphenyl)-1,3,2,4-diphosphetane-2,4-disulfide] and thelike. As the reactive derivatives of the compounds of the generalformula (VIII), mention is made of acid halides, acid anhydrides mixedacid anhydrides, C₁₋₅ alkyl esters, benzylesters and so on.

The reaction of a compound of the general formula (IV) with a thionationreagent usually proceeds in a solvent inert to the reaction (pyridine,dimethylaniline, benzene, toluene, xylene, tetrahydrofuran, chloroform,dioxane, etc. or a mixed solvent thereof) at a temperature ranging from30° C. to 100° C. for 30 minutes to 5 hours.

The reaction of a compound of the general formula (V) with a compound ofthe general formula (VI) usually proceeds in a solvent inert to thereaction (benzene, toluene, xylene, tetrahydrofuran, dioxane, etc. or amixed solvent thereof in the presence of an organic acid (acetic acid,propionic acid etc.), an inorganic acid (hydrochloric acid, sulfuricacid etc.) or silica gel at a temperature ranging from room temperatureto the refluxing temperature of the solvent used for 30 minutes to 5hours.

The reaction of a compound of the general formula (V) with hydrazinehydrate usually proceeds in a solvent inert to the reaction (methanol,ethanol, propanol, isopropyl alcohol, butanol, etc.) at a temperatureranging from 0° C. to 40° C. for about 5 minutes to about 3 hours.

The reaction of a compound of the general formula (VII) with a compoundof the general formula (VIII) or its reactive derivative or a compoundof the general formula (IX) proceeds in a solvent inert to the reaction(benzene, toluene, xylene, tetrahydrofuran, dioxane, etc. or a mixedsolvent thereof) in the presence of an organic acid (acetic acid,propionic acid, etc.), an inorganic acid (hydrochloric acid, sulfuricacid, etc.) or silica gel at a temperature ranging from room temperatureto the refluxing temperature of the solvent used for 30 minutes to 6hours.

The thus obtained compounds of the general formula (I) can be separatedfrom the reaction mixture and purified by the per se known methods suchas recrystallization and chromatography.

The compounds of the general formula (I) can be converted into theirsalts by the treatment with an inorganic acid (hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), anorganic acid (acetic acid, propionic acid, succinic acid, glycolic acid,lactic acid, malic acid, tataric acid, citric acid, maleic acid, fumaricacid, methanesulfonic acid, p-toluenesulfonic acid, ascorbic acid,etc.), an inorganic base (sodium hydroxide, potassium hydroxide, calciumhydroxide, magnesium hydroxide, zinc hydroxide, ammonium hydroxide,etc.), an organic base (methylamine, diethylamine, triethylamine,dicyclohexylamine, triethanolamine, ethylenediamine,trishydroxymethylaminomethane, quinine, cinchonine, etc.) or an aminoacid (lysine, ornithine, arginine, guanidine).

Among the compounds of the present invention, those having a chiralcarbon can be usually obtained as racemic bodies. The racemic bodies canbe resolved into their optical isomers. These optical isomers can alsobe produced by using the optically active starting compounds. Theindividual diastereomers can be purified by preparativerecrystallization or chromatography.

The compounds encompassed in the present invention are exemplified bythe following.

    __________________________________________________________________________     ##STR7##                                                                     Ar    R.sup.1                                                                           R.sup.2                                                                          R.sup.3                                                                          R.sup.4                                                                              X        p m.p. (°C.)                           __________________________________________________________________________    2-ClPh                                                                              Et  H  NNC(Me)   2-Indolyl                                                                              0 284˜286 (d)                           2-ClPh                                                                              Et  H  NNC(Me)   3-Indolyl                                                                              1 259                                         2-ClPh                                                                              Et  H  NNC(Pr)   2-Indolyl                                                                              0 265˜266                               2-ClPh                                                                              Et  H  NNC(Pr)   2-Naphthyl                                                                             0 226˜227                               2-ClPh                                                                              Et  H  O  Me     2-Indolyl                                                                              0 257˜259 (d)                           2-ClPh                                                                              Et  H  O  Me     3,4-diClPh                                                                             0 180˜181                               2-ClPh                                                                              Et  H  NNC(Me)   2-Naphthyl                                                                             0                                             2-NO.sub.2 Ph                                                                       Et  H  NNC(Me)   2-Indolyl                                                                              0                                             4-MePh                                                                              Et  H  NNC(Me)   2-Indolyl                                                                              0                                             2-ClPh                                                                              Et  H   NNCH     2-Indolyl                                                                              0 287˜288 (d)                           Ph    Et  H  NNC(Me)   2-Indolyl                                                                              0                                             2-ClPh                                                                              Me  Me NNC(Me)   2-Indolyl                                                                              0                                             2-ClPh                                                                              (CH.sub.2).sub.4                                                                     NNC(Me)   2-Indolyl                                                                              0 304˜306 (d)                           Ph    H   H  NNC(Me)   2-Indolyl                                                                              0                                             2-ClPh                                                                              Me  Me O  Me     2-Indolyl                                                                              0                                             2-ClPh                                                                              (CH.sub.2).sub.4                                                                     O  Me     2-Indolyl                                                                              0                                             4-MeOPh                                                                             Me  Me NNC(Me)   2-Indolyl                                                                              0                                             2-ClPh                                                                              Et  H  NNCH      2-Naphthyl                                                                             0                                             2-ClPh                                                                              Me  Me NNC(Me)   2-Indolyl                                                                              0                                             Ph    Cl  H  NNC(Me)   2-Indolyl                                                                              0                                             Ph    Et  H  O  CH.sub.2 COOH                                                                        2-Indolyl                                                                              0                                             2-MeOPh                                                                             Et  H  NNC(Me)   2-Indolyl                                                                              0                                             2,4-diClPh                                                                          Et  H  NNC(Me)   2-Indolyl                                                                              0                                             3,4-diClPh                                                                          Et  H  NN C(Me)  2-Indolyl                                                                              0                                             3-Py  Et  H  NNC(Me)   2-Indolyl                                                                              0                                             2-ClPh                                                                              Et  H  NNC(Me)   2-Thienyl                                                                              0                                             2-ClPh                                                                              Et  H  NNC(Me)   2-Pyridyl                                                                              0                                             2-ClPh                                                                              Et  H  NNC(Me)   2-Benzimidazolyl                                                                       0                                             2-ClPh                                                                              Et  H  NNC(Me)   2-Benzofuranyl                                                                         0                                             2-ClPh                                                                              Et  H  NNC(Me)   2-Benzothiazolyl                                                                       0                                             2-ClPh                                                                              Et  H  NNC(Me)   3,4-diClPh                                                                             0 254˜255                               __________________________________________________________________________

In Table, Cl means chlorine, Et means ethyl, Me means methyl, MeO meansmethoxy, NO₂ means nitro, Ph means phenyl, Pr means propyl, Py meanspyridyl and (d) means decomposition point.

The starting compounds of the general formula (II) are novel and can beproduced, for example, in the following manner.

By reacting a compound of the general formula ##STR8## wherein each ofthe symbols is as defined above with a dialkyl carbonate (e.g. diethylcarbonate) in the presence of a base (sodium hydride, potassiumtert-butoxide, etc.), an alkoxycarbonyl group (ethoxycarbonyl, etc.) isintroduced at the 6-position of the compound (X), and the thus-obtainedcompound is reacted with a 0-(2,4-dinitrophenyl)hydroxylamine to give acompound of the general formula ##STR9## wherein R⁹ stands for an alkyland the other symbols are as defined above and the thus-obtainedcompound of the general formula (XI) is subjected to hydrolysis in thepresence of a base (e.g. sodium hydroxide, potassium hydroxide, bariumhydroxide) in water or a mixture of water and an organic solvent(preferably, methanol, ethanol, diethyl ether, tetrahydrofuran, dioxane,etc.) at a temperature ranging from about 0° C. to the boiling point ofthe solvent used to give the reaction mixture, which is rendered acidicwith the use of an acid such as hydrochloric acid, hydrobromic acid,hydrofluoric acid, sulfuric acid, trifluoroacetic acid ortrifluoromethanesulfonic acid to give a compound of the general formula(II).

Since the compounds of the present invention and their salts possessexcellent antagonistic actions to cholestokinin and gastrin and potentand durable pancreatic enzyme- and gastric acid-secretion-suppressiveactions, they are useful as the medicaments acting on the centralnervous and peripheral nervous systems and the prophylactic andtherapeutic medicines for pancreatic disorders and gastrointestinalulcers.

Below, shown are the pharmacological actions of the compound of thepresent invention.

The compound of the present invention used for the test is as follows:

Compound A:4-(2-Chlorophenyl)-2-ethyl-6-(2-indolecarboxamido)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine

Also as the control compounds, there were used CCK-8, CCK-4 and thefollowing compound.

L-364718:N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide

EXPERIMENTAL EXAMPLE 1 Effects on gastric excreting capability (Gastricemptying test)

The solutions of the test compounds were orally administered to male ddYmice weighing about 20 g, and 25 minutes after the oral adminstration,CCK-8 was subcutaneously administered at the dose of 30 μg/kg. At 5minutes' lapse thereafter, 0.1 ml of a 1.5% aqueous solution of methylcellulose containing 0.05% phenolred (Sigma) was orally administered.After 15 minutes, the stomach was extracted and the gastric contentswere mixed with a 10% aqueous solution of trichloroacetic acid. Afterthe removal of the proteins, the residue was centrifuged at 3000 rpm for10 minutes. To the supernatant was added a 1N solution of sodiumhydroxide and the mixture was again centrifuged. Thereafter, OD₅₆₀ valueof the supernatant was measured by the spectrophotometer (Hitachi 200-10type) to estimate the minimum effective dose (MED).

The results are tabulated in Table 1.

EXPERIMENTAL EXAMPLE 2 CCK receptor-binding

The entire pancreas of a male mongrel adult dog was extracted and thefat tissues thereof were removed. The residual portion was homogenizedin 50 mM tris hydrochloride (pH 7.5) (Blinkman·Polytron PT20). After thefiltration with nylon cloth (120 mesh) followed by centrifugation(50,000×g, for 12 minutes), the obtained sediment was homogenized in atris buffer solution in the same manner as mentioned above and thehomogenate was centrifuged. The obtained sediment was suspended in abuffer solution for binding assay (5 mM magnesium chloride, chloride, 5mM dithiothreitol, 2 mg/ml bovine serum albumin, 0.1 mg/ml bacitracin,and 50 mM tris hydrochloride, pH 7.2), containing 0.14 mg/mltrypsin-inhibitor (soy bean), and the suspension was used as thereceptor source.

The binding assay was conducted by adding 50 μl of buffer solution (forthe entire binding), unmarked CCK-8 sulfate (for the non-specificbinding) or test compound (for the measurement of binding-inhibitorycapability of ¹²⁵ I-CCK) of the final concentration of 1 μM and 50 μl of¹²⁵ I-CCK-8 (63-67 TBq/mmol, 40,000-50,000 cpm) to 450 μl of membranesuspension (containing 100 μg of proteins), incubating the reactionmixture at 20° C. for 30 minutes, suction-filtering the mixture withglass fibre filter paper (Whatmann G/FB), washing three times with 2.5ml per each tube of an ice-cooled tris buffer solution immediately afterthe suction-filtration and measuring the radio activity concentration onthe filter paper.

The effect of the test compound on binding to CCK receptor was estimatedby the concentration at which the specific binding is 50% suppressed(IC₅₀, nM) based on the inhibitory rate calculated in accordance withthe following formula. ##EQU1##

The results are tabulated in Table 1.

                  TABLE 1                                                         ______________________________________                                                Gastric Emptying                                                                          CCK binding, IC.sub.50  (nM)                              Test Compound                                                                           MED (mg/kg p.o.)                                                                            Pancreas   Brain                                      ______________________________________                                        A         0.3-1.0       0.60       1.80                                       L-364718  0.1-0.3       0.60       85.00                                      CCK-8     --            0.60       0.50                                       CCK-4     --            800.00     83.00                                      ______________________________________                                    

EXPERIMENTAL EXAMPLE 3 Acute toxicity test

The acute toxicity of the compounds of the present invention was studiedwith the use of 6 male mice. After the test Compound A was orallyadministered to the mice and the mice were observed for consecutive 5days, it was found that the Compound A had low toxicity.

When the compounds of the present invention and their pharmaceuticallyacceptable salts are used as medicaments, they are usually admixed withpharmaceutically acceptable additives such as carriers, excipients,diluents and solubilizing agents (lactose, corn starch, talc, kaolin,physicological saline, sterilized water etc.) and safely administered topatients in forms such as tablets (including sugar-coated tablets andfilm-coated tablets), capsules, powders, injections, instillations,suppositories and cataplasms.

While the dosage varie depending upon the sex difference, age,body-weight, symptom and so on of patients, the preferable daily dosagefor oral administration, is usually in the range from about 1 to about500 mg per adult man.

The present invention is specifically explained by working examples andexamples for the preparation of starting compounds, to which the presentinvention is, needless to say, not limited.

Starting Compound-Preparation Example 1

To 500 ml of diethyl carbonate were added 22.0 g of4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepineand 4.3 g of sodium hydride, and the mixture was heated. Hydrogen gasbegan to generate at about 100° C., while the solution gradually coloredviolet. After 30 minutes' reflux, the mixture was cooled to 20° C.,whereto 16.0 g of O-(2,4-dinitrophenyl)hydroxylamine was added. Themixture was stirred for 2 hours. After the completion of the reaction,the reaction mixture was poured into ice-water containing 6 ml of aceticacid. The diethyl carbonate layer was separated, washed twice with waterand dried over anhydrous magnesium sulfate. Diethyl carbonate wasdistilled off under reduced pressure, and diisopropyl ether was added tothe obtained residue to separate crystals, which were collected byfiltration. The crystals were recrystallized from ethyl acetate to give18.2 g of ethyl6-amino-4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine-6-carboxylate,m.p. 180°-181° C.

In a mixture of 180 ml of ethanol and 60 ml of water was dissolved 15.1g of ethyl6-amino-4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-carboxylate.To the solution was added 6.0 g of crystals of barium hydroxide·8hydrate, and the mixture was stirred at room temperature for 24 hours.After the solvent was distilled off under reduced pressure, 200 ml ofwater and 100 ml of benzene were added and the mixture was stirredfully. The water layer was separated, adjusted to pH 2 with 1Nhydrochloric acid and left standing still for 24 hours. Thereafter, themixture was neutralized with sodium carbonate, and the precipitatedcrystals were collected by filtration. The obtained crystals weredissolved in chloroform and insoluble matters were filtered off. Afterthe solvent was distilled off under reduced pressure, the residue wasrecrystallized from ethanol to give 10.7 g of 6-amino-4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine,m.p. 130°-131° C.

EXAMPLE 1

To 120 ml of tetrahydrofuran were added 5.0 g of6-amino-4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,2.7 g of indole-2-carboxylic acid, 4.3 g of 2-chloro-N-methyl pyridiniumiodide and 6.2 g of dibutyl amine, and the mixture was heated underreflux while stirring for 90 minutes. After the solvent was distilledoff under reduced pressure, the residue was washed with diisopropylether. Ethanol was added to separate crystals, which were collected byfiltration. The thus-obtained crystals were recrystallized fromchloroform-ethanol to give 4.9 g of4-(2-chlorophenyl)-2-ethyl-6-(2-indolecarboxamido)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,m.p. 284°-286° C. (decomposition).

EXAMPLE 2

In 20 ml of chloroform was dissolved 1.5 g of6-amino-4-(2-chlorophenyl)-2-ethyl-9-propyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine,and 0.47 g of triethylamine was added to the solution. A solution of0.89 g of naphthalene-2-carbonyl chloride in 10 ml of chloroform wasadded dropwise to the mixture at not more than 10° C. The mixture wasfurther stirred for 1 hour at room temperature and washed with 0.1Nhydrochloric acid, 0.1N sodium hydroxide and a saturated solution ofsodium chloride in order. Thereafter, the solvent was distilled offunder reduced pressure, and the residue was washed with diisopropylether. Ethanol was added to yield crystals, which were collected byfiltration. The crystals were recrystallized from chloroform-ethanol togive 1.4 g of4-(2-chlorophenyl)-2-ethyl-6-(2-naphthalenecarboxamido)-9-propyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,m.p. 226°-227° C.

EXAMPLE 3

By following the procedure in Example 1 with the use of6-amino-4-(2-chlorophenyl)-2-ethyl-9-propyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepineand indole-2-carboxylic acid, obtained was4-(2-chlorophenyl)-2-ethyl-6-(2-indolecarboxamido)-9-propyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,m.p. 265°-266° C.

EXAMPLE 4

In the same manner as in Example 1 with the use of6-amino-4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepineand indole-3-acetic acid, obtained was4-(2-chlorophenyl)-2-ethyl-6-(3-indoleactamido)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,m.p. 259° C.

EXAMPLE 5

By following the procedure in Example 1 with6-amino-4-(2-chlorophenyl)-2-ethyl-8-methyl-8H-6,7-dihydro-thieno[3,2-f][1,4]diazepin-7-oneand indole-2-carboxylic acid, obtained was4-(2-chlorophenyl)-2-ethyl-6-(2-indolecarboxamido)-8-methyl-8H-6,7-dihydro-thieno[3,2-f][1,4]diazepin-7-one,m.p. 257°-259° C. (decomposition).

EXAMPLE 6

By following the procedure in Example 2 with6-amino-4-(2-chlorophenyl)-2-ethyl-8-methyl-8H-6,7-dihydro-thieno[3,2-f][1,4]diazepineand 3,4-dichlorobenzoyl chloride, obtained was4-(2-chlorophenyl)-2-ethyl-6-(3,4-dichlorobenzoylamino)-8-methyl-8H-6,7-dihydro-thieno[3,2-f][1,4]diazepin-7-one,m.p. 180°-181° C.

While the present invention has been described by the foregoingspecification including working examples, the embodiment describedherein can be changed and modified in various manners within the scopeand the spirit of the present invention.

We claim:
 1. A thienodiazepine compound of the general formula ##STR10##wherein R¹ and R² are the same or different and respectively represent ahydrogen, a halogen, a C₁₋₂₀ alkyl or an aralkyl selected from the groupconsisting of benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl,4-phenylbutyl, 1-naphthylmethyl and 2-naphthylmethyl unsubstituted orsubstituted on the aromatic ring by one to three substituent(s) selectedfrom the group consisting of halogen, alkyl, alkoxy, trifluoromethyl,nitro, amino, cyano and hydroxy, or wherein R¹ and R² together form aring selected from the group consisting of a cyclopentene ring, acyclopentadiene ring, a cyclohexene ring, a cyclohexadiene ring, abenzene ring, a cycloheptene ring, a cycloheptadiene ring and acycloheptatriene ring; R³ represents an oxygen, R⁴ represent a hydrogen,a C₁₋₂₀ alkyl, a C₂₋₈ alkenyl or a group of the formula --(CH₂)_(m)COOR⁶ (wherein R⁶ represents a hydrogen atom, a C₁₋₂₀ alkyl, a C₂₋₈alkenyl or an aralkyl selected from the group consisting of benzyl,1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,1-naphthylmethyl and 2-naphthylmethyl unsubstituted or substituted onthe aromatic ring by one to three substituent(s) selected from the groupconsisting of halogen, alkyl, alkoxy, trifluoromethyl, nitro, amino,cyano and hydroxy, and m represents an integer of 1-6), or R³ and R⁴together form a group of the formula ═N--N═C(R⁵)--,wherein R⁵ representsa hydrogen, a C₁₋₂₀ alkyl, a C₂₋₈ alkenyl, an aralkyl selected from thegroup consisting of benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl and 2-naphthylmethylunsubstituted or substituted on the aromatic ring by one to threesubstituent(s) selected from the group consisting of halogen, alkyl,alkoxy, trifluoromethyl, nitro, amino, cyano and hydroxy, or a group ofthe formula --(CH₂)_(n) COOR⁷ (wherein R⁷ represents a hydrogen, a C₁₋₂₀alkyl, a C₂₋₈ alkenyl or an aralkyl selected from the group consistingof benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,1-naphthylmethyl and 2-naphthylmethyl unsubstituted or substituted onthe aromatic ring by one to three substituent(s) selected from the groupconsisting of halogen, alkyl, alkoxy, trifluoromethyl, nitro, amino,cyano and hydroxy, and n represents an integer of 1-6); Ar and X are thesame or different and respectively represent an aryl selected from thegroup consisting of a phenyl, a phenyl substituted by 1 or 2substituents selected from the group consisting of halogen, alkyl,alkoxy and nitro, and a 2-naphthyl or a heteroaryl selected from thegroup consisting of a pyridyl, an indolyl, a thienyl, a benzofuranyl, a1H-benzimidazol-2-yl and a 2-benzothiazolyl; and p represents an integerof 1-6, or its salt.
 2. A compound as claimed in claim 1 which isselected from a group consisting of the followingcompounds:4-(2-chlorophenyl)-2-ethyl-6-(2-indolecarboxamido)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,4-(2-chlorophenyl)-2-ethyl-6-(2-naphthalenecarboxamido)-9-propyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,4-(2-chlorophenyl)-2-ethyl-6-(2-indolecarboxamido)-9-propyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,4-(2-chlorophenyl)-2-ethyl-6-(3-indoleacetamido)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,4-(2-chlorophenyl)-2-ethyl-6-(2-indolecarboxamido)-8-methyl-8H-6,7-dihydro-thieno[3,2-f][1,4]diazepin-7-one4-(2-chlorophenyl)-2-ethyl-6-(3,4-dichlorobenzoylamino)-8-methyl-8H-6,7-dihydro-thieno[3,2-f][1,4]diazepin-7-one,4-(2-chlorophenyl)-2-ethyl-6-(2-indolecarboxamido)-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,6-(2-chlorophenyl)-7,8,9,10-tetrahydro-4-(2-indolecarboxamido)-1-methyl-4H-(1)benzothieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepineand4-(2-chlorophenyl)-2-ethyl-6-(3,4-dichlorobenzoylamino)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.3. A pharmaceutical composition which comprises a therapeuticallyeffective amount of a compound as claimed in claim 1 and apharmaceutically acceptable additive.